EP3681881A1 - Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques mutagènes et fibrotiques - Google Patents

Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques mutagènes et fibrotiques

Info

Publication number
EP3681881A1
EP3681881A1 EP18779987.9A EP18779987A EP3681881A1 EP 3681881 A1 EP3681881 A1 EP 3681881A1 EP 18779987 A EP18779987 A EP 18779987A EP 3681881 A1 EP3681881 A1 EP 3681881A1
Authority
EP
European Patent Office
Prior art keywords
heteroaryl
azabicyclo
aryl
optionally substituted
heptan
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP18779987.9A
Other languages
German (de)
English (en)
Other versions
EP3681881B1 (fr
Inventor
Jianhua Chao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ardelyx Inc
Original Assignee
Ardelyx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ardelyx Inc filed Critical Ardelyx Inc
Publication of EP3681881A1 publication Critical patent/EP3681881A1/fr
Application granted granted Critical
Publication of EP3681881B1 publication Critical patent/EP3681881B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention is directed to modulators of a nuclear hormone receptor, farnesoid
  • FXR X receptor
  • the invention is related to compounds and compositions which modulate FXR, methods of treating diseases or disorders associated with FXR, and methods of synthesis of these compounds.
  • FXR is a ligand-activated transcription factor. Upon binding of a ligand, FXR either binds to DNA at the FXR response elements (FXREs) as a monomer, or forms a heterodimer with retinoid X receptor (RXR) and then binds to FXREs, regulating the transcription of a variety of target genes.
  • FXREs FXR response elements
  • RXR retinoid X receptor
  • FXR target genes that are involved in a wide range of physiological functions including bile acid homeostasis (i.e., BACS, BAAT, BSEP, FGF15/19, etc.), cholesterol and lipoprotein metabolism (i.e., Apolipoprotein C- I, II, IV, Apolipoprotein E, MDR3, Human complement C3, ApoA-1, hepatic lipase, SREPB- lc), glucose metabolism (i.e., PEPCK, GSK3, AKR1B7, GLUT4, G6Pase), and xenobiotics metabolism (i.e., GST ⁇ 3, GST ⁇ 4, GST ⁇ 1, GST ⁇ 3, SULT1A1, SULT1A2).
  • BACS bile acid homeostasis
  • BAAT i.e., BAAT, BSEP, FGF15/19, etc.
  • lipoprotein metabolism i.e., Apolipoprotein C- I, II, IV, Apolipoprotein E, MDR3,
  • FXR a regulator of cellular inflammatory and immune responses.
  • Activation of FXR can provide anti -inflammatory effects by negative regulation of nuclear factor ⁇ (NFKB) pathway, reducing the expression of NFKB and the many pro-inflammatory cytokines associated with this pathway (Matsubara, T. et al., "FXR signaling in the enterohepatic system," Mol. Cell Endocrinol. 2013, 368, 17-29; Moschetta, A., "Deciphering the nuclear bile acid receptor FXR paradigm, " Nucl. Recept.
  • NFKB nuclear factor ⁇ pathway
  • FXR plays a key role in the synthesis, transport and metabolism of bile acids (BAs) and the many physiological and pathophysiological conditions that involve BAs.
  • BAs bile acids
  • activation of FXR has been shown to lead to the increased expression of short heterodimer partner (SHP), which in turn inactivates liver receptor homolog-1 (LRH-1) and inhibits the cholesterol 7- alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the first step of biosynthesis of primary bile acids from cholesterol, thereby reduces the production of bile acids.
  • SHP short heterodimer partner
  • LH-1 liver receptor homolog-1
  • CYP7A1 cholesterol 7- alpha-hydroxylase
  • FXR farnesoid X receptor in inflammation and resolution
  • FXR Activation of FXR has been shown to repress the FKB pathway, a prototypical proinflammatory signaling pathway, and inhibit the expression of key cytokines such as T F ⁇ , IL- ⁇ , and IL-6.
  • cytokines such as T F ⁇ , IL- ⁇ , and IL-6.
  • proinflammatory cytokines e.g., TNF ⁇ , IL- ⁇ , IFNy
  • profibrotic genes ⁇ i.e., Collagen al, TIMP-1, and aSMA
  • FXR activators has the potential to be a treatment for a range of diseases including bile acid related disorders, metabolic syndrome, type-2-diabetes, hyperlipidemia, hypertriglyceridemia, primary biliary cirrhosis (PBC), fatty liver disease, nonalcoholic steatohepatitis (NASH), inflammatory autoimmune diseases, Crohn's disease, multiple sclerosis, atherosclerosis, hepatic and colon cancers, and other disorders.
  • PBC primary biliary cirrhosis
  • NASH nonalcoholic steatohepatitis
  • known FXR activators have demonstrated toxicities, treatment limiting adverse effects, and other issues. For these reasons, there remains a need for novel and potent small molecule FXR activators. Summary of the Invention
  • one of X 1 or X 2 is NR X or N + (O-)Rx and the other is CHR y or C(O);
  • Yi, Y 2 , Y 3 and Y 4 are independently C, CH or N, wherein one of Yi and Y 4 is substituted with R3 and the other is substituted with ring A;
  • R y is H, alkyl, cycloalkyl or cycloalkylalkyl wherein said alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;
  • L 2 is a bond or -S(O) 2 -;
  • A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl,
  • heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;
  • B is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one
  • R 1 and R 2 are each independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R 9 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same carbon atom form a spirocycloalkyl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same atom form a spiroheterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they
  • heterocycloalkyl when on non-adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ;
  • R 3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, or cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and -OH;
  • R 4 is COOR 6a , -(CH 2 ) n -COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) deliberatelyCOOR 6a ,
  • each R 5 is independently at each occurrence halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, spiroheterocycloalkyl, -O-cycloalkyl, -O-heterocycloalkyl, aryl, heterocycloalkyl, or heteroaryl wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and halo
  • R 6a is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 6b R 6c , SO 2 NR 6b R 6c , and -OH;
  • R 6b and R 6c are each independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH;
  • R 6d is alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, -O-CO-alkyl, -O-COcycloalkyl, -O-CO-alkyl- COOH, R 6 R 6c , R 6f CO-alkyl, R 6f CO-alkoxy, cycloalkyl, heterocycloalkyl and -OH;
  • R 6e is -OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH;
  • R 6f is alkyl or haloalkyl
  • R 6g is H or alkyl optionally substituted with -O-CO-alkyl; each R 7 is independently at each occurrence OH, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN; each R 8 is independently at each occurrence alkyl, alkoxy,
  • haloalkyl haloalkoxy, halogen, or -OH
  • each R 9 is independently at each occurrence alkyl, alkoxy,
  • haloalkyl haloalkoxy, halogen, or -OH
  • n 0, 1, or 2;
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;
  • p 1 or 2.
  • Another aspect of the invention relates to a method of treating a disease or disorder in which FXR plays a role.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders in which FXR plays a role an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention is directed to a method of modulating FXR.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention is directed to a method of activating FXR.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of treating a liver disease.
  • the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of treating an intestinal disease.
  • the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of treating a kidney disease.
  • the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of treating an autoimmune disorder.
  • the method comprises administering to a patient in need of a treatment for an autoimmune disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of treating cancer.
  • the method comprises administering to a patient in need of a treatment for cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a liver disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an intestinal disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a kidney disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an autoimmune disorder.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease associated with activating FXR.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease in which FXR plays a role.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a liver disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an intestinal disease. Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a kidney disease. Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an autoimmune disorder.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of cancer.
  • the present invention further provides methods of treating a disease or disorder associated with modulation of FXR including, but not limited to, liver diseases, intestinal diseases, kidney disease, autoimmune disorders, or cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • a disease or disorder associated with modulation of FXR including, but not limited to, liver diseases, intestinal diseases, kidney disease, autoimmune disorders, or cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention provides activators of FXR that are therapeutic agents in the treatment of diseases, such as liver diseases, intestinal diseases, kidney disease, autoimmune disorders, and cancer.
  • diseases such as liver diseases, intestinal diseases, kidney disease, autoimmune disorders, and cancer.
  • the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with the modulation of FXR.
  • the present invention relates to compounds and compositions that are capable of modulating the activity of FXR.
  • the invention features methods of treating, preventing or ameliorating a disease or disorder in which FXR plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a
  • the methods of the present invention can be used in the treatment of a variety of FXR dependent diseases and disorders by increasing the activity of nuclear receptor FXR. Activation or modulation of FXR provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, liver diseases, intestinal diseases, kidney diseases, autoimmune disorders, and cancer.
  • an element means one element or more than one element.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • optionally substituted means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 - C 6 ) haloalkoxy, (C 3 -C 7 ) cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -O-(C 2 -C 6 ) alkenyl, -O- (C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -
  • Optionally substituted as used herein also refers to substituted or unsubstituted whose meaning is described below.
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, - H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl, -C(O)(C 1 -C 6 ) alkyl, - OC(O)0(C 1 -C 6 ) alkyl, - H 2 , H((C 1 -C 6 ) alkyl), N((C 1 -C 6 ) alkyl) 2 , -S(O) 2 -(C 1 -C 6 ) alkyl,
  • an aryl group herein defined may be fused to an unsaturated or partially saturated ring, or fused with a fully saturated ring.
  • exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from the group consisting of N, O, and S, the remaining ring atoms being C.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from the group consisting of N, O, and S.
  • the aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2- b] thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2- a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-
  • heteroaryl groups herein defined may be fused to an unsaturated or partially saturated ring containing a heteroatom selected from N, O and S; or fused with a fully saturated ring containing a heteroatom selected from N, O and S.
  • Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl,
  • dihydrobenzothiophenyl dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H ⁇ isoquinolinyl, 2, 3 -dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.
  • Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl either alone or in combination with other groups (e.g. alkoxy, haloalkyl and the like) refers to a straight or branched chain saturated, unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms.
  • Examples of a (C 1 -C 6 ) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • "alkyl" is fully saturated.
  • Alkoxy refers to a straight or branched chain saturated or unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl).
  • alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. In an embodiment, "alkoxy" is fully saturated.
  • Alkoxyalkoxy refers to an alkoxy group as defined herein which is substituted with an alkoxy group e.g., -0(alkyl)-O-(alkyl). Examples of alkoxyalkoxy groups include without limitation, methoxymethoxy, ethoxyethoxy, propoxymethoxy, or ethoxym ethoxy.
  • Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups examples include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined, may be straight or branched.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the "alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propanyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • Cycloalkyl or “carbocyclyl” means monocyclic or polycyclic saturated or unsaturated (fully or partially) non-aromatic carbon rings containing 3-18 carbon atoms.
  • Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or
  • a C 3 -C 8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
  • a cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane). In an embodiment, "cycloalkyl" is fully saturated.
  • Heterocyclyl or “heterocycloalkyl” monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms.
  • heterocycloalkyl comprises one or two 4- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
  • "heterocycle” or “heterocycloalkyl” is fully saturated.
  • hydroxyalkyl means an alkyl group as defined above, where the alkyl group is substituted with one or more -OH groups.
  • hydroxyalkyl groups include HO-
  • hydroxyalkyl is fully saturated.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. In an embodiment, "haloalkyl" is fully saturated.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • haloalkoxy is fully saturated.
  • cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C ⁇ N.
  • Spirocycloalkyl or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P).
  • a (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • One or more of the carbon atoms can be substituted with a heteroatom.
  • "spirocycloalkyl" or “spirocyclyl” is fully saturated.
  • spiroheterocycloalkyl or "spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl).
  • heterocycle e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl.
  • spiroheterocycloalkyl or
  • GW4064 is an FXR agonist compound having the following structure.
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • isomer refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties.
  • the structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light
  • stereoisomers With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laur
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • an "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • treating refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • disorder is used herein to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administered refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • autoimmune disease includes, but is not limited to, the following
  • autoimmune diseases Amyotrophic Lateral Sclerosis (ALS), Autoimmune Atherosclerosis, Autoimmune Diabetes Insipidus, Autoimmune Gastritis, Autoimmune Hepatitis, Autoimmune Interstitial Cystitis, Autoimmune Uveitis, Autoimmune Vasculitis, Behcet's Disease, Celiac Disease, Chronic Fatigue Syndrome, Crohn's Disease, chronic active hepatitis, Diabetes
  • kidney disease includes, but is not limited to the following kidney diseases: fibrotic renal disease and diabetic nephrophathy.
  • liver disease includes, but is not limited to, the following liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, portal vein hypertension (PAH), obesity and Type 2 Diabetes.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • alcoholic liver disease intra- and extra-cholestasis
  • PAH portal vein hypertension
  • obesity Type 2 Diabetes
  • intestinal disease includes, but is not limited to the following intestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease and bile acid diarrhea.
  • cancer includes, but is not limited to, the following cancers: hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, gastric cancer, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, bile duct carcinoma, renal carcinoma, breast cancer, and Barett's esophagus, and combinations thereof.
  • the present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein or receptor.
  • the invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating FXR.
  • the present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein.
  • the invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating
  • compounds of the invention have the structure of Formula (I):
  • one of X 1 or X 2 is NR X or N + (O-)Rx and the other is CHR y or C(O);
  • Y 1 , Y 2 , Y 3 and Y 4 are independently C, CH or N, wherein one of Yi and Y 4 is substituted with R3 and the other is substituted with ring A;
  • R y is H, alkyl, cycloalkyl or cycloalkylalkyl wherein said alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;
  • L 2 is a bond or -S(O) 2 -;
  • A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;
  • B is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more
  • R 1 and R 2 are each independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R 9 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same carbon atom form a spirocycloalkyl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same atom form a spiroheterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they
  • heterocycloalkyl when on non-adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ; cycloalkyl ring optionally substituted with one or more R 8 ; or when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ;
  • R 3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, or cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and -OH;
  • R 4 is COOR 6a , -(CH 2 ) n -COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) structuriCOOR 6a , CONH(CH 2 ) crampR 6a , -(CH 2 ) supplementCONH(CH 2 ) resortR 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) friendshipR 6d , -(CH 2 ) admir- CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) noiN(CO)R 6d CONH(CH 2 ) crampSO 2 R 6e , COR 6f , (CH 2 ) favorPO(OR 6g ) 2 , COO(CH 2 ) procurPO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) favorCOOR 6a , SO 2 R 6e , CN, -(CH 2 ) favour-NR 6b C(
  • each R 5 is independently at each occurrence halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;
  • R 6a is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 6b R 6c and -OH;
  • R 6b and R 6c are each independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH;
  • R 6d is alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, -O-CO-alkyl, -O-COcycloalkyl, -O-CO-alkyl- COOH, NR 6b R 6c , NR 6f CO-alkyl, NR 6f CO-alkoxy, cycloalkyl, heterocycloalkyl and -OH;
  • R 6e is -OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and -OH;
  • R 6f is alkyl or haloalkyl
  • R 6g is H or alkyl optionally substituted with -O-CO-alkyl; each R 7 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN; each R 8 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or - OH; each R 9 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or - OH; m is 0, 1, or 2; n is 1, 2, 3, or 4; and p is 1 or 2.
  • compounds of the invention have the Formula (I)
  • one of X 1 or X 2 is NR X and the other is CH 2 ;
  • Yi, Y 2 , Y 3 and Y 4 are independently C, CH or N, wherein one of Yi and Y 4 is substituted with R3 and the other is substituted with ring A;
  • L 2 is a bond or -S(O) 2 -;
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl, wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 ;
  • R 1 and R 2 are each independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl,
  • R 4 is COOR 6a , CO R 6 R 6c , CO H(CH 2 ) crampCOOR 6a , CO R 6 SO 2 R 6d , CO H(CH 2 ) obligeSO 2 R 6e , CN, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; each R 5 is independently at each occurrence halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, CN, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl
  • R 6a is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6
  • R 6 and R 6c are each independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl,
  • R 6d is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 )
  • R 6e is -OH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -
  • X 1 is CHR y or C(O) and X 2 is NR X or N + (O-)Rx. In an embodiment, X 1 is CHR y and X 2 is NR X or N + (O-)Rx. In an embodiment, X 1 is C(O) and X 2 is NR X or N + (O-)Rx. In an embodiment, X 1 is CHR y and X 2 is NR X . In an embodiment, X 1 is C(O) and X 2 is NR X . In an embodiment, X 1 is CHR y and X 2 is N + (O-)Rx.
  • X 1 is C(O) and X 2 is N + (O-)Rx.
  • X 1 is CH 2 and X 2 is NR X .
  • X 1 is NR X or N + (O-)Rx and X 2 is CHR y or C(O).
  • X 1 is NRx and X 2 is CHR y or C(O).
  • X 1 is N + (O-)Rx and X 2 is CHR y or C(O).
  • X 1 is NR X and X 2 is CHR y .
  • X 1 is NR X and X 2 is C(O).
  • X 1 is N + (O-)Rx and X 2 is CHR y .
  • X 1 is N + (O-)Rx and X 2 is CHR y .
  • X 1 is N + (O-)Rx and X 2 is CHR y .
  • X 1 is N + (O-)Rx
  • X 1 is N + (O-)Rx and X 2 is C(O). In another embodiment, X 1 is NR X and X 2 is CH 2 .
  • L 2 is a bond. In another embodiment L 2 is - S(O) 2 -.
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
  • A is (C 3 -C 8 ) cycloalkyl.
  • A is (C 3 -C 8 ) cycloalkyl substituted with one or more R 7 .
  • A is (C 6 -C 10 ) aryl.
  • A is (C 6 -C 10 ) aryl substituted with one or more R 7 .
  • A is phenyl optionally substituted with one or more R 7 .
  • A is phenyl unsubstituted by R 7 while R 1 and R 2 are both a halogen. In another embodiment, A is phenyl unsubstituted by R 7 while R 1 and R 2 are both a CI at the ortho positions relative to the isoxazole ring.
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 . In another embodiment, A is heterocycloalkyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 7 .
  • A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
  • A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 7 .
  • A is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl or heterocycloalkyl are optionally substituted with one or more R 7 .
  • A is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heteroaryl is optionally substituted with one or more R 7 .
  • A is (C 3 - C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl, wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
  • A is (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heterocycloalkyl are optionally substituted with one or more R 7 .
  • B is (C 6 -C 10 ) aryl optionally substituted with one or more R 5 .
  • B is heteroaryl comprising one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 5 .
  • B is (C 6 -C 10 ) aryl.
  • B is (C 6 -C 10 ) aryl substituted with one or more R 5 .
  • B is heteroaryl.
  • B is heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 5 .
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl are substituted with one or more R 5 .
  • R 1 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 1 is halogen, CN, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 - C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 1 is (C 1 -C 6 ) alkyl, (C 1 - C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 1 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 1 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 1 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 1 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In another embodiment, R 1 is H, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 1 is (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 1 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 1 is H, (C 1 - C 6 ) haloalkyl, or halogen.
  • R 1 is (C 1 -C 6 ) haloalkyl or halogen.
  • R 2 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 2 is halogen, CN, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 - C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 2 is (C 1 -C 6 ) alkyl, (C 1 - C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 2 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 2 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 2 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 2 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In another embodiment, R 2 is H, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 2 is (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
  • R 2 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
  • R 2 is H, (C 1 - C 6 ) haloalkyl, or halogen.
  • R 2 is (C 1 -C 6 ) haloalkyl or halogen.
  • R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring.
  • R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring substituted with one to three R 8 .
  • R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 )
  • R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring.
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring.
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring.
  • R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring substituted with one to three R 8 .
  • R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring.
  • A when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring.
  • A when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring.
  • R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring substituted with one to three R 8 .
  • R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 .
  • R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one to three R 8 .
  • R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring.
  • when cycloalkyl or heterocycloalkyl when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring.
  • R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring substituted with one to three R 8 .
  • R 3 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 - C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 3 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 - C 4 ) alkynyl, or. (C 1 -C 4 ) alkoxy.
  • R 3 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or (C 1 -C 4 ) hydroxyalkyl.
  • R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen and (C 1 -C 6 ) alkyl.
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 6 ) alkyl.
  • R 4 is COOR 6a , -(CH 2 ) n -COOR 6a ,
  • R 4 is COOR 6a .
  • R 4 is -alkyl-COOR 6a .
  • R 4 is -(CH 2 ) n -COOR 6a
  • R 4 is CONR 6b OH.
  • R 4 is CONR 6b R 6c .
  • R 4 is CONH(CH 2 ) n COOR 6a .
  • R 4 is CONH(CH 2 ) n SO 2 R 6e .
  • R 4 is
  • R 4 is CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , -(CH 2 ) n CONH(CH 2 ) n R 6a .
  • R 4 is CONH(CH 2 ) n R 6a .
  • R 4 is -(CH 2 ) n CONH(CH 2 ) n R 6a .
  • R 4 is CONR 6b SO 2 R 6d .
  • R 4 is -(CH 2 ) n - NR 6b C(O)R 6c .
  • R 4 is -(CH 2 ) n -N(OH)-C(O)R 6c .
  • R 4 is -alkyl-CONR 6b SO 2 R 6d .
  • R 4 is COR 6f ,
  • R 4 is COO(CH 2 ) n PO(OR 6g ) 2 .
  • R 4 is SO 2 NR 6b (CH 2 ) n COOR 6a .
  • R 4 is SO 2 R 6e .
  • R 4 is oxo.
  • R 4 is (C 3 -C 8 ) cycloalkyl optionally substituted with (CH 2 ) radicalCOOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) complicatCOOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) anythingSO 2 R 6e , COR 6f , (CH 2 ) administratPO(OR 6g ) 2 , COO(CH 2 ) administratPO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e .
  • R 4 is heterocycloalkyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; and said heterocycloalkyl is optionally substituted with (CH 2 ) n COOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) favorCOOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) favorSO 2 R 6e , COR 6f , (CH 2 ) dislikePO(OR 6g ) 2 , COO(CH 2 ) consumerPO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) favorCOOR 6a , SO 2 R 6e .
  • R 4 is or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; and said said heteraryl is optionally substituted with (CH 2 ) n COOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) favorCOOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) favorSO 2 R 6e , COR 6f , (CH 2 ) dislikePO(OR 6g ) 2 , COO(CH 2 ) consumerPO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) favorCOOR 6a , SO 2 R 6 .
  • R 4 is or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; and said said heteraryl is optionally substituted
  • R 4 is COOR 6a ,
  • R 4 is COOR 6a ,
  • R 4 is COOR 6a
  • R 4 is COOR 6a , CONR 6b SO 2 R 6d , CONR 6b R 6c , or heterocycloalkyl comprising one 5- to 7-membered ring and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • R 4 is COOR 6a , CONR 6b SO 2 R 6d , or heterocycloalkyl comprising one 5- to 7-membered ring and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • R 4 is COOR 6a , CONR 6b SO 2 R 6d , or heterocycloalkyl comprising one 5- to 7- membered ring and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • R 4 is CONH(CH 2 ) n COOR 6a or CONH(CH 2 ) n SO 2 R 6e .
  • R 4 is CONR 6b R 6c or CONH(CH 2 ) n COOR 6a .
  • R 4 is CO R 6 SO 2 R 6d or CO H(CH 2 ) disguiseSO 2 R 6e .
  • n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4.
  • R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, CN, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl,
  • R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) haloalkoxy.
  • R 5 is (C 3 -C 8 ) cycloalkyl, (C 6 - C10) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) haloalkoxy.
  • R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
  • R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy.
  • R y is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl,
  • R y is H. In an embodiment R y is methyl. In an embodiment R y is ethyl. In an embodiment R y is CF 3 . In an embodiment R y is (C 1 -C 6 ) alkyl. In an embodiment R y is (C 1 -C 6 ) haloalkyl.
  • R y is alkoxyalkyl.
  • R 6a is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl
  • R 6a is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
  • R 6a is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6a is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • the heterocycloalkyl comprises one or two 5- to 7-membered rings and
  • R 6a is H or (C 1 -C 4 ) alkyl. In some embodiments of the Formulae above, R 6 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl,
  • substituents each independently selected from the group consisting of halogen, (C 1 -
  • R 6 is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
  • R 6 is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6 is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6 is H or (C 1 -C 4 ) al
  • R 6c is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy
  • R 6c is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
  • R 6c is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6c is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6c is H or (C 1 -C 4 )
  • R 6d is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) al
  • R 6d is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6
  • R 6d is (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
  • R 6d is (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6d is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • the heterocycloalkyl comprises one or two 5- to 7-membered rings and
  • R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more -OH. In another embodiment, R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
  • R 6e is -OH, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) al
  • R 6e is -OH, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • the heterocycloalkyl comprises one or two 5- to 7-membered rings and
  • R 6e is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 6 -C 10 ) aryl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 - C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • substituents each independently selected from the group consisting of halogen, (C 1 - C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl or heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
  • R 6e is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more -OH.
  • R 6e is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
  • R 6e is -OH, (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
  • R 6f is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl. In another embodiment, R 6f is (C 1 -C 6 ) alkyl. In another embodiment, R 6f is methyl. In another embodiment, R 6f is (C 1 - C 6 ) haloalkyl. In another embodiment, R 6f trifluorom ethyl. In some embodiments, R 6g is H or (C 1 -C 6 ) alkyl optionally substituted with -O-CO-(C 1 - C 6 ) alkyl. In an embodiment, R 6g is H.
  • R 6g is (C 1 -C 6 ) alkyl optionally substituted with -O-CO-(C 1 -C 6 ) alkyl. In an embodiment, R 6g is -CH 2 -O-C(O)-C(CH ) .
  • R 7 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 - C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or CN.
  • R 7 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or CN.
  • R 7 is (C 1 -C 4 ) alkyl, (C 2 -C4) alkenyl, (C 2 -C4) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • R 7 is (C 1 -C 4 ) alkyl, (C 2 -C4) alkenyl, (C 2 -C4) alkynyl, or (C 1 -C 4 ) alkoxy.
  • R 7 is (C 1 -C 4 ) alkyl, (C 2 -C4) alkenyl, (C 2 -C4) alkynyl, (C 1 -C 4 ) alkoxy, or halogen.
  • R 7 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
  • R 7 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
  • R 7 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • R 8 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, or -OH.
  • R 8 is halogen, or -OH.
  • R 8 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 8 is (C 1 - C4) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, halogen, or -OH.
  • R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • R 9 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, or -OH.
  • R 9 is halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 9 is (C 1 - C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, halogen, or -OH.
  • R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or -OH.
  • m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 1 or 2. In another embodiment, m is 0 or 1.
  • p is 1. In another embodiment, p is 2.
  • A is (C 6 -C 10 ) aryl, (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is (C 6 -C 10 ) aryl or (C 3 -C 8 ) cycloalkyl.
  • A is (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is phenyl or (C 3 -C 8 ) cycloalkyl.
  • A is phenyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • A is phenyl.
  • A is cyclohexyl, bicyclo[2.2.2.]octanyl, or
  • A is cyclohexyl or bicyclo[2.2.2.]octanyl. In another embodiment, A is bicyclo[2.2.2.]octanyl, or spiro[2.5]octanyl. In yet another embodiment, A is cyclohexyl, bicyclo[2.2.2.]octanyl, or tetrahydropyranyl. In another embodiment, A is cyclohexyl. In yet another embodiment, A is bicyclo[2.2.2.]octanyl. In another embodiment, A is tetrahydropyranyl.
  • R 1 and R 2 are each independently H, halogen, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 ) haloalkoxy.
  • R 1 and R 2 are each independently H, halogen, or (C 1 -C 6 ) haloalkyl.
  • R 1 and R 2 are each independently halogen or (C 1 -C 6 ) haloalkyl.
  • R 1 is H and R 2 is halogen, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy.
  • R 1 is H and R 2 is (C 1 -C 6 ) haloalkyl or (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is H and R 2 is (C 1 -C 6 ) haloalkyl. In yet another embodiment, R 1 is H and R 2 is (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is halogen and R 2 is halogen, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy. In yet another embodiment, R 1 is halogen and R 2 is (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is halogen and R 2 is (C 1 -C 6 ) haloalkyl. In yet another embodiment, R 1 is halogen and R 2 is halogen.
  • B is unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
  • B is heteroaryl comprising one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
  • B is unsubstituted (C 6 -C 10 ) aryl.
  • B is (C 6 -C 10 ) aryl optionally substituted with (C 1 -C 6 ) alkyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
  • B is pyrimidinyl, furanyl, benzo[d]thiazolyl, 1- methyl-1H-benzo[d]imidazolyl, 1 -methyl- 1H-indolyl, benzo[d]isoxazolyl, 2,2-difluoro-l- methylindolin-3-onyl, or 7-fluoro-l -methyl- 1H-benzo[d]imidazolyl, wherein each B is optionally substituted with one or more halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 ) haloalkyl.
  • R 3 is (C 3 -C 8 ) cycloalkyl optionally substituted with halogen or (C 1 -C 6 ) alkyl. In another embodiment, R 3 is (C 3 -C 8 ) cycloalkyl optionally substituted with halogen. In another embodiment, R 3 is unsubstituted (C 3 -C 8 ) cycloalkyl.
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 - C10) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl.
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 )
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl.
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • A is heterocycloalkyl wherein the
  • heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloal
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) halo
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalky
  • L 1 is -(CH2) P - and L 2 is a bond.
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond and
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
  • Li is -(CH 2 ) P -, L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - Cio) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 )
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 )
  • L 1 is a -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 )
  • L 1 is -(CH 2 ) P - and L 2 is a bond.
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
  • Li is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , and B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or (C 6 -C 10 ) aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is a -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH2) P -
  • L 2 is a bond
  • A is (C 3 - C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is halogen or (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is halogen or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C
  • L 1 is - (CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , and B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH2) P -
  • L 2 is a bond
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is halogen or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is halogen or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 1 is -(CH 2 )
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH2) P -
  • L 2 is a bond
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 3 is (C 1 -C 4 ) alkyl or (C 3
  • L 1 is -(CH 2 ) P -, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • Li is -(CH 2 ) P -, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 - C4) haloalkoxy, and R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 )
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
  • L 1 is -(CH 2 ) P -
  • L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -, L 2 is a bond,
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - Cio) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or
  • R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 - C 4 ) alkyl.
  • L 1 is -(CH 2 ) P -, L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1
  • L 1 is -(CH2) P -, L 2 is a bond
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 - C 4
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the
  • heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - Cio) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H
  • L 2 is - S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is
  • L 2 is - S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is hal
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 2 is - S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl.
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 3 is (C 1
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is(C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the
  • heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4
  • L 1 is -(CH 2 ) P - and L 2 is -S(O) 2 -.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
  • Li is -(CH 2 ) P -, L 2 is -S(O) 2 -, A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 , and B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7- membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - Cio) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH2) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 - C
  • L 1 is a -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6- member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1
  • L 1 is -(CH2) P - and L 2 is -S(O) 2 -.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • L 1 is -(CH 2 ) P -
  • L 2 is - S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is a -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 - C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 - C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -
  • L 2 is - S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 - C 8 ) cycloalkyl optionally substituted with one or more R 7 .
  • L 1 is - (CH 2 )p-
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 1 is -(CH2) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
  • R 2 is halogen or (C 1 -C 4 ) haloalkyl
  • R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 6 - C10) aryl optionally substituted with one or more R 7 .
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is -(CH 2 ) P -
  • L 2 is - S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4
  • heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 3 is (C 1 -C 4 ) al
  • L 1 is -(CH2) P -
  • L 2 is -S(O) 2 -
  • A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • Li is -(CH 2 ) P -, L 2 is -S(O) 2 -, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 - C4) haloalkoxy, and R 3 is (C 1 -C 4 ) alkyl or (C 3 ) alky
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
  • L 1 is - (CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - Cio) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) hal
  • L 1 is -(CH2) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 - C10) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1- 4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl,
  • L 1 is -(CH 2 ) P -
  • L 2 is -S(O) 2 -
  • A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
  • B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
  • R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 - C4) haloalkyl, or (C 1 -C 4 ) haloalkoxy
  • R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl
  • compounds of Formula (I) have the structure of Formula (la) - (Id):
  • the compounds of the invention have the stereochemical configuration of Formula (la). In an embodiment, the compounds of the invention have the stereochemical configuration of Formula (lb). In an embodiment, the compounds of the invention have the stereochemical configuration of Formula (Ic). In an embodiment, the compounds of the invention have the stereochemical configuration of Formula (Id).
  • the compounds of Formula (I) have the structure of Formula (Ila) -
  • the compounds of the invention have the structure of Formula (Ila). In an embodiment, the compounds of the invention have the structure of Formula (lib). In an embodiment, the compounds of the invention have the structure of Formula (lie). In an embodiment, the compounds of the invention have the structure of Formula (lid).
  • the compounds of Formula (I) have the structure of Formula (llal) -
  • the compounds of the invention have the structure of Formula (Hal).
  • the compounds of the invention have the structure of Formula (Ilbl).
  • the compounds of the invention have the structure of Formula (IIcl).
  • the compounds of the invention have the structure of Formula (Ildl).
  • the compounds of Formula (I) have the structure of Formula (Ilia) or (Illg):
  • the compounds of the invention have the structure of Formula (Ilia). In an embodiment, the compounds of the invention have the structure of Formula (Illb). In an embodiment, the compounds of the invention have the structure of Formula (IIIc). In an embodiment, the compounds of the invention have the structure of Formula (llld). In another embodiment, the compounds of Formula (I) have the structure of Formula
  • the compounds of the invention have the structure of Formula (IVa). In an embodiment, the compounds of the invention have the structure of Formula (IVb). In an embodiment, the compounds of the invention have the structure of Formula (IVc). In an embodiment, the compounds of the invention have the structure of Formula (IVd).
  • the compounds of Formula (I) have the structure of Formula (Va) or (Vd):
  • the compounds of the invention have the structure of
  • the compounds of the invention have the structure of Formula (Vb).
  • the compounds of the invention have the structure of Formula (Vc).
  • the compounds of the invention have the structure of Formula (Vd).
  • the compounds of Formula (I) have the structure of Formula (Via) or (VId):
  • the compounds of the invention have the structure of Formula (Via). In an embodiment, the compounds of the invention have the structure of Formula (VIb). In an embodiment, the compounds of the invention have the structure of
  • Formula (Vic) In an embodiment, the compounds of the invention have the structure of Formula (VId). In another embodiment, the compounds of Formula (I) have the structure of Formula (Vila) or (Vlld):
  • the compounds of the invention have the structure of Formula (Vila). In an embodiment, the compounds of the invention have the structure of Formula (Vllb). In an embodiment, the compounds of the invention have the structure of Formula (VIIc). In an embodiment, the compounds of the invention have the structure of Formula (Vlld).
  • the compounds of Formula (I) have the structure of Formula (Villa) or (Vllld):
  • the compounds of the invention have the structure of Formula (Villa). In an embodiment, the compounds of the invention have the structure of Formula (Vlllb). In an embodiment, the compounds of the invention have the structure of Formula (VIIIc). In an embodiment, the compounds of the invention have the structure of Formula (VllId).
  • the compound is selected from the group consisting of the group consisting of:
  • the compounds of the invention may contain further asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
  • the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
  • the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also
  • the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • the compounds of Formula I may form salts, solvates, polymorphs and isotopologues which are also within the scope of this invention.
  • Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the compounds of the present invention can be prepared in a number of ways from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes well known to those skilled in the art of organic synthesis.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by the steps outlined in the General Schemes below which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
  • Y 1 -Y 4 , A, B, and R ⁇ -R 4 are defined as in herein.
  • dichloromethane also affords the intermediate Id.
  • Deprotection intermediate If provides the desired product lg of Formula (I).
  • Analagous compounds of Formula (I) wherein the azabicyclo[2.2. ljheptane is attached at the 6-position can also be synthesized as described in General Scheme 1 by using an N-protected 2- azabicyclo[2.2.1]heptan-6-ol in place of intermediate lb.
  • thionyl chloride in the presence of benzotriazole, a brominating agent (i.e. CBr 4 in the presence of triphenylphosphine), and or iodination agent (i.e. methyltriphenylphosphine iodide) in a solvent (i.e., DCM, THF, DMF).
  • a basic condition i.e. NaH
  • a solvent i.e. DMF
  • a palladium catalyst and ligand i.e., palladium (II) acetate (Pd(OAc) 2 ) and Xantophos
  • mild base i.e. Cs 2 CO 3
  • the coupling of g1il or g1i2 with g1j, wherein R 4 in reagent g1j is optionally protected is effected by the treatment with a base (i.e. CsF, Cs 2 CO 3 ) in a solvent (i.e. DMSO, DMF) at optionally at elevated temperature to afford the desired product of Formula (I) when when R 4 is unprotected, or advanced intermediate g1kl or g1k2 when R 4 is protected.
  • a base i.e. CsF, Cs 2 CO 3
  • a solvent i.e. DMSO, DMF
  • Deprotection of intermediate g1kl or g1k2 provides the desired product of Formula (I).
  • R is an alkyl group
  • X is halogen (i.e., F, CI, Br, I) or another suitable leaving group (i.e., mesylate)
  • PG is a protecting group (i.e., tert-butylcarbamate (BOC), benzylcarbamate (Cbz)).
  • Boronic acid g2c couples with iodo-pyrazole intermediate g2b in the presence of a palladium catalyst and ligand (i.e. Pd 2 (dba) 3 , Sphos) under mild basic condition (i.e. K3PO4) in a solvent (i.e.
  • intermediate g2hl or g2h2 i.e., when PG is an acid labile group, i.e., Cbz
  • a strong acid i.e., HC1
  • a Lewis acid i.e. TMSI
  • DCM dichloromethane
  • R is an alkyl group
  • X is halogen (i.e., F, CI, Br, I) or another suitable leaving group (i.e., mesylate)
  • PG is a protecting group (i.e., tert-butylcarbamate (BOC), benzylcarbamate (Cbz)).
  • R is an alkyl group
  • X is halogen (i.e., F, CI, Br, I) or another suitable leaving group (i.e., mesylate)
  • PG is a protecting group (i.e., tert-butylcarbamate (BOC), benzylcarbamate (Cbz)).
  • Another aspect of the invention is directed to a method of modulating FXR.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention is directed to a method of modulating FXR.
  • the method comprises administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the invention is directed to a method of activating FXR.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the invention is directed to a method of activating FXR.
  • the method involves administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
  • the method comprises
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • Another aspect of the invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
  • the method comprises
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • Another aspect of the invention relates to a method of modulating FXR. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • Another aspect of the invention relates to a method of modulating FXR.
  • the method comprises administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the activation of FXR, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • Another aspect of the present invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the activation of FXR, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating a liver disease.
  • the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating a liver disease.
  • the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating an intestinal disease.
  • the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating an intestinal disease.
  • the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating a kidney disease.
  • the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating a kidney disease.
  • the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating an autoimmune disease.
  • the method comprises administering to a patient in need of a treatment for an autoimmune disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating an autoimmune disease.
  • the method comprises administering to a patient in need of a treatment for an autoimmune disease an effective amount of a
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating cancer.
  • the method comprises administering to a patient in need of a treatment for cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the present invention relates to a method of treating, preventing, inhibiting, or eliminating cancer.
  • the method comprises administering to a patient in need of a treatment for cancer an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a disease or disorder in which FXR plays a role.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a disease or disorder in which FXR plays a role.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a liver disease.
  • a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the treatment, prevention, inhibition, or elimination of a disease associated with activating FXR.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a liver disease.
  • the present invention relates to a compound of Formula (I) or (la), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of an intestinal disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of an intestinal disease.
  • the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a kidney disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a kidney disease.
  • the present invention relates to a compound of Formula (I) or (la), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of an autoimmune disorder.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of an autoimmune disorder.
  • the present invention relates to a compound of Formula (I) or (la), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of cancer.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of cancer.
  • Another aspect of the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder or cancer.
  • Another aspect of the present invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
  • the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder or cancer.
  • the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a liver disease.
  • the present invention relates to the use of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a liver disease.
  • the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an intestinal disease.
  • the present invention relates to the use of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an intestinal disease.
  • the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a kidney disease.
  • the present invention relates to the use of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a kidney disease.
  • the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an autoimmune disease.
  • the present invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an autoimmune disease.
  • the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a cancer.
  • the present invention relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a cancer.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
  • a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in the manufacture of a medicament for treating a liver disease.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a liver disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an intestinal disease.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating an intestinal disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a kidney disease.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a kidney disease.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an autoimmune disorder.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating an autoimmune disorder.
  • Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating cancer.
  • the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a liver disease.
  • the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of an intestinal disease.
  • the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a kidney disease.
  • the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of an autoimmune disorder. In other embodiments, the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a cancer.
  • the present invention also relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition in which FXR plays a role, wherein the medicament comprises a compound of Formula (I).
  • the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by FXR, wherein the medicament comprises a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the disease or condition is selected from the group consisting of liver disease, intestinal disease, kidney disease, an autoimmune disorder, or cancer.
  • the disease can be any disease including, but not limited to, Alagille syndrome (ALGS), atherosclerosis, biliary atresia, Byler disease, gallstone disease, hyperlipidemia, hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, obesity, type-2 diabetes mellitus, and gastric cancer.
  • AGS Alagille syndrome
  • atherosclerosis atherosclerosis
  • biliary atresia Byler disease
  • gallstone disease gallstone disease
  • hyperlipidemia hepatocellular carcinoma
  • hepatocellular adenoma cholangiocarcinoma
  • colorectal cancer colorectal adenoma
  • the liver disease can be any liver diseases, including, but not limited to, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, biliary atresia, portal vein hypertension (PAH), spontaneous bacterial peritonitis (SBP), acute decompensation liver failure, hepatorenal syndrome and hepatic encephalopathy.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • alcoholic liver disease intra- and extra-cholestasis
  • PAH portal vein hypertension
  • SBP spontaneous bacterial peritonitis
  • acute decompensation liver failure hepatorenal syndrome and he
  • the liver disease is NASH and the compound of the invention is administered in combination with an anti-inflammatory agent or anti-fibrotic agent.
  • the intestinal disease can be any intestinal disease, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease and bile acid diarrhea.
  • the disease is an intestinal permeability disease, disorder or condition mediated by tight junction dysfunction.
  • the disease, disorder or condition is gastric ulcers, infectious diarrhea, irritable bowel syndrome, functional GI diseases (IBS, IBS-C, IBS-D, IBS-M, post infectious IBS), inflammatory bowel disease (CD, UC), Celiac's, cancer (colorectal), Leaky Gut Syndrome, cystic fibrosis GI manifestations, multi-organ failure, microscopic colitis or necrotizing enterocolitis.
  • compounds of the invention are used to treat one of the following disease, disorder or condition: allergy e.g. atopy, food allergy; infections e.g.
  • autoimmune disease e.g. type 1 diabetes, celiac disease, multiple sclerosis, IBD, ankylosing spondylitis, RA, lupus, alopecia areata, rheumatoid arthritis, polymyalgia
  • rheumatica multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria (hives) and
  • the kidney disease can be any kidney disease, including, but not limited to, fibrotic renal disease and diabetic nephrophathy.
  • the autoimmune disorder can be any autoimmune disorder, including, but not limited to, inflammatory bowel disease, autoimmune hepatitis, autoimmune liver disease (primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)), and multiple sclerosis.
  • the cancer can be any cancer including, but not limited to, a cancer is selected from the group consisting of hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, or gastric cancer.
  • the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, of the present invention and a pharmaceutically acceptable carrier used for the treatment of diseases including, but not limited to liver diseases, intestinal diseases, kidney diseases, autoimmune disorders or cancer.
  • compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • a disease or disorder in which FXR plays a role including a liver disease, an intestinal disease, a kidney disease or an autoimmune disorder comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).
  • One therapeutic use of the compounds or compositions of the present invention which activate FXR is to provide treatment to patients or subjects suffering from a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
  • the disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a
  • a pharmaceutically acceptable carrier such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate,
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.
  • Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
  • polydihydropyrans polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the disclosed compounds, when used for the indicated effects range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition.
  • compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • Example 1 Intermediate. Benzyl (lS,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2- carboxylate (C-1) and (1S,4R,6S)-Benzyl 6-hydroxy-2-aza-bicyclo [2.2.1 ]heptane-2- carboxylate (C-2)
  • Example 2 Intermediate. Benzyl (lR,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2- carboxylate (C-4) and Benzyl (lR,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2- carbox late (C-5)
  • Step 2 Benzyl (lS,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-3)
  • benzyl (1S,4S,5S)-5-[(4- nitrophenyl)carbonyloxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate C-3a (1.6 g, 4.04 mmol, 1.0 equiv.) in methanol/H 2 O (20 mL / 2 mL) and LiOH.H 2 O (1.69 g, 40.28 mmol, 10.0 equiv.).
  • Example 3 Intermediates. Benzyl (lR,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2- carboxylate (C-4) and Benzyl (lR,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2- carboxylate (C-5)
  • the resulting white suspension was filtered through a Celite pad and the pad was washed with anhydrous THF (250.0 mL).
  • the clear filtrate was cooled to 0 °C and then treated with trimethylamine (12.8 mL, 91.6 mmol) and CbzCl (10.3mL, 68.7 mmol).
  • the reaction mixture was slowly warmed to room temperature and stirred for 48 hours.
  • the white precipitate was filtered and the resulting clear filtrate solution was concentrated to dryness.
  • Step 1 To a 1L round bottom flask was added a solution of (1S,4R)-2-azabicyclo[2.2.1]hept-5- en-3-one C-la (30 g, 274.9 mmol, 1.00 equiv.) in N,N-dimethylformamide (500 mL). The solution was cooled to 0°C. Sodium hydride (12 g, 300.0 mmol, 1.10 equiv., 60% dispersion in mineral oil) was added in several batches at 0°C. The reaction mixture was stirred for another 30 min at 0°C. To this mixture was added TBAI (10 g, 27.1 mmol, 0.10 equiv.).
  • Step 2 To a 500 mL round bottom flask purged with and maintained under an inert atmosphere of nitrogen was added a solution of (1S,4R)-2-[(4-methoxyphenyl)methyl]-2- azabicyclo[2.2.1]hept-5-en-3-one C-7a (12.2 g, 53.21 mmol, 1.00 equiv.) in anhydrous dimethoxyethane (120 mL). The solution was cooled to 0°C. A solution of borane-dimethyl sulfide complex (11.6 mL, 10 M in DMS, 2.18 equiv.) was added dropwise with stirring at 0°C.
  • the crude product was purified by high pressure (maximum: 20 MPa) Prep-flash using the following conditions: Column, Welch Ultimate® XB-C18 OBD Column, 10 urn, 50*250mm (300 g); mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 30.0% in 40 min); Detector, UV 254nm, to provide (1 S,4R,5R)-5-hydroxy-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[2.2. l]heptan-3-one C-7 (4.6 g, 35%, with a longer retention time than isomer C-8) as a white solid.
  • Step 1 To a 100 mL round-bottom flask was added sodium hydride (6.25 g, 260.42 mmol, 2.00 equiv., 60% dispersed in mineral oil) followed by toluene (40 mL). The mixture was cooled to - 10°C. A solution of ethyl l,3-dithiane-2-carboxylate la (15 g, 78.00 mmol, 1.00 equiv.) and (bromomethyl)cyclopropane (11.5 g, 85.18 mmol, 1.10 equiv.) in N,N-dimethylformamide (20 mL) was added slowly with stirring.
  • Step 2 To a 100 mL round-bottom flask was added BS (17g, 95.52 mmol, 6.00 equiv.) followed by the addition of MeCN (88 mL) and H 2 O (22 mL). The mixture was cooled to 0°C, and added with a solution of ethyl 2-(cyclopropylmethyl)-l,3-dithiane-2-carboxylate lb (4 g, 16.23 mmol, 1.00 equiv.) in MeCN (10 mL) in 5 min.
  • Step 3 To a 50 mL round-bottom flask was added ethyl 3-cyclopropyl-2-oxopropanoate lc (5 g, 32.01 mmol, 1.00 equiv.) and (dimethoxymethyl)dimethylamine (10 mL). The resulting mixture was stirred for 18 h at 20°C and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (0% to 10%). Removal of solvents afforded ethyl 3-cyclopropyl-4-(dimethylamino)-2-oxobut-3-enoate Id (2.7 g, 40%) as light yellow oil. Step 4.
  • the aqueous mixture was extracted with ethyl acetate (300 mL x 2); and combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum.
  • the residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (0% to 15%) to afford ethyl 4-cyclopropyl-l-(2,6-dichlorophenyl)-1H- pyrazole-5-carboxylate 1e (3.3 g, 47%) as a light yellow oil.
  • Step 5 To a 100 mL round-bottom flask was added ethyl 4-cyclopropyl-l-(2,6-dichlorophenyl)- 1H-pyrazole-5-carboxylate 1e (2.302 g, 7.08 mmol, 1.00 equiv.) and tetrahydrofuran (20 mL). The mixture was cooled at 0°C, L1AIH4 (540 mg, 14.23 mmol, 2.00 equiv.) was added in several batches. The reaction mixture was stirred at room temperature for 2h and then diluted with 20 mL of EA. The reaction was quenched by the addition of 30 mL of ice water.
  • L1AIH4 540 mg, 14.23 mmol, 2.00 equiv.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with an aqueous solution of sodium potassium tartrate (50 mL) and brine (30 mL x 2). The organic solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl
  • Step 6 To a 50 mL round-bottom flask was added benzotriazole (332 mg, 1.00 equiv.) and dichloromethane (10 mL). The mixture was cooled to 0°C, thionyl chloride (665 mg, 2.00 equiv.) was added slowly, and the reaction mixture was stirred for 30 min at 0°C. [4- cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methanol 1f (790 mg, 2.79 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at room temperature overnight.
  • Step 7 To a 100 mL round-bottom flask was added 5-(chloromethyl)-4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazole lg (470 mg, 1.56 mmol, 1.00 equiv.), N,N-dimethylformamide (10 mL), and TBAI (581 mg, 1.57 mmol, 1.00 equiv.).
  • Step 8 To a 100 mL round-bottom flask was added benzyl (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2. l]heptane-2-carboxylate lh (420 mg, 0.82 mmol, 1.00 equiv.), dichloromethane (4 mL), and TMSI (328 mg, 1.64 mmol, 2.00 equiv.). The resulting mixture was stirred for 10 min at room temperature and then quenched by the addition of 1 mL of a 1 M hydrogen chloride aqueous solution.
  • Step 9 To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy]-2-azabicyclo[2.2.
  • the aqueous mixture was extracted with ethyl acetate (50 mL x 2), and the combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19* 150mm; mobile phase, Water (0.05% TFA) and ACN (5.0% ACN up to 45.0% in 1 min, up to 63.0% in 7 min);
  • Step 1 To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy]-2-azabicyclo [2.2.1] heptane li (200 mg, 0.53 mmol, 1.00 equiv.), toluene (5 mL), Pd(OAc) 2 (25 mg, 0.11 mmol, 0.20 equiv.), Xantphos (64 mg, 0.11 mmol, 0.20 equiv), Cs 2 CO 3 (518 mg, 1.59 mmol, 3.00 equiv.), and tert-butyl 4-bromo-2-fluorobenzoate (134 mg, 0.49 mmol, 1.10 equiv.).
  • Step 2 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 2a (176 mg, 0.31 mmol, 1.00 equiv.), dichloromethane (3 mL), and
  • Example 8 4-[(lS,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy ⁇ -2-azabicyclo[2.2.1]heptan-2-yl]-2,6-difluorobenzoic acid (1-3)
  • Step 1 To a 50 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane li (117 mg, 0.31 mmol, 1.00 equiv.), toluene (3 mL), methyl 4-bromo-2,6-difluorobenzoate (85 mg, 0.34 mmol, 1.10 equiv.), Ruphos precatalyst (53 mg, 0.06 mmol, 0.20 equiv.), Ruphos (29 mg, 0.06 mmol, 0.20 equiv.), and Cs 2 CO 3 (303 mg, 0.93 mmol, 3.00 equiv.).
  • Step 2 To a 50 mL round-bottom flask was added methyl 4-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,6- difluorobenzoate 3a (100 mg, 0.18 mmol, 1.00 equiv.), LiOH (73 mg, 3.05 mmol, 10.00 equiv.), methanol (2 mL), and water(0.2 mL). The resulting mixture was stirred at 50°C for 2h.
  • Step 1 To a 50 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane li (100 mg, 0.26 mmol, 1.00 equiv.), MeCN (2 mL), TEA (53 mg, 0.52 mmol, 2.00 equiv.), and methyl 6- fluoropyridine-3-carboxylate (82 mg, 0.53 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight, and quenched with the addition of water (30 mL).
  • the aqueous mixture was extracted with ethyl acetate (50 mL x 2), and the combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 2 To a 50 mL round-bottom flask was added methyl 6-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3- carboxylate 4a (100 mg, 0.19 mmol, 1.00 equiv.), methanol (2 mL), LiOH (78 mg, 3.26 mmol, 10.00 equiv), and water(0.2 mL). The resulting mixture was heated at 60°C for 2h.
  • Step 7 To a 8 mL sealed tube was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6-dichlorophenyl)- 1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane li (270 mg, 0.71 mmol, 1.00 equiv.), methyl 5-fluoropyridine-2-carboxylate (222 mg, 1.43 mmol, 2.00 equiv.), MeCN (3 mL), and TEA (193 mg, 1.91 mmol, 2.00 equiv.). The resulting mixture was heated at 90°C for 3 days. After cooling to room temperature, water (50 mL) was added.
  • Step 2 To a 25 mL round-bottom flask was added methyl 5-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-2- carboxylate 5a (140 mg, 0.27 mmol, 1.00 equiv.), methanol (2 mL), water (1 mL), and lithium hydroxide monohydrate (115 mg, 2.74 mmol, 10.00 equiv.). The resulting mixture was stirred at 60°C for lh.
  • the pH value of the solution was adjusted to 4 using a 1M HC1 aqueous solution.
  • the aqueous mixture was extracted with ethyl acetate (150 mL x 2), and the combined organic extracts were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column,, 5um, 19* 150mm; mobile phase, Water(0.05%TFA ) and ACN (20.0% ACN up to 50.0% in 8 min); Detector, uv 254/220nm.
  • Step 1 To a 25 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane li (156 mg, 0.41 mmol, 1.00 equiv.), Ruphos precatalyst (66 mg, 0.20 equiv.), Ruphos (37 mg, 0.20 equiv.), Cs 2 CO 3 (390 mg, 1.20 mmol, 3.00 equiv.), methyl 5-bromopyrimidine-2-carboxylate (129 mg, 0.59 mmol, 1.50 equiv.), and toluene (2 mL).
  • the resulting mixture was heated at 110°C overnight. After cooling to room temperature, the mixture was diluted with 30 mL of H 2 O, extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated.
  • the mixture was diluted with 20 mL of H2O, and the pH value of the solution was adjusted to 3 using a 1M hydrogen chloride aqueous solution.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions Column, XB ridge Shield RP18 OBD Column,, 5um,19* 150mm; mobile phase, Water(0.05%TFA) and ACN (30.0% ACN up to 50.0% in 8 min); Detector, UV 254/220nm.
  • Example 12 4-[(lS,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dimethylphenyl)-1H-pyrazol-5- yl] methoxy ⁇ -2-azabicyclo [2.2. l]heptan-2-yl]-2-fluorobenzoic acid (1-7)
  • Step 1 To a 250 mL round-bottom flask was added (2,6-dimethylphenyl)hydrazine (1.25 g, 9.18 mmol, 1.00 equiv.), hydrogen chloride (0.9 mL), ethanol (10 mL), and ethyl (3Z)-3-cyclopropyl- 4-(dimethylamino)-2-oxobut-3-enoate Id (1.3 g, 6.15 mmol, 1.10 equiv.). The resulting mixture was heated at 85°C overnight and concentrated under vacuum. The residue was diluted with 50 mL of H 2 O, and extracted with ethyl acetate (100 mL x 2).
  • Step 2 To a 250 mL round-bottom flask was added ethyl 4-cyclopropyl-l-(2,6-dimethylphenyl)- 1H-pyrazole-5-carboxylate 7a (600 mg, 2.11 mmol, 1.00 equiv.), DIBAL (3.5 mL, 2.00 equiv.), and tetrahydrofuran (6 mL). The resulting mixture was stirred at room temperature overnight, and quenched by the addition of 10 mL of sodium hydroxide.
  • Step 3 To a 250 mL round-bottom flask was added [4-cyclopropyl-l-(2,6-dimethylphenyl)-1H- pyrazol-5-yl]methanol 7b (380 mg, 1.57 mmol, 1.00 equiv.), thionyl chloride (371 mg, 2.00 equiv), benzotriazole (185 mg, 1.00 equiv), and dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 2h.
  • Step 4 To a 50 mL round-bottom flask was added 5-(chloromethyl)-4-cyclopropyl-l-(2,6- dimethylphenyl)-1H-pyrazole 7c (100 mg, 0.38 mmol, 1.00 equiv.), benzyl (1S,4S,5R)-5- hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate C-l (114 mg, 0.46 mmol, 1.20 equiv.), N,N- dimethylformamide (2 mL), and sodium hydride (20 mg, 60% dispersion in mineral oil, 0.83 mmol, 2.00 equiv.).
  • reaction mixture was stirred at room temperature overnight, then quenched by the addition of 10 mL of water.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated.
  • Step 5 To a 50 mL round-bottom flask was added benzyl (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dimethylphenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2. l]heptane-2-carboxylate 7d (250 mg, 0.53 mmol, 1.00 equiv.), TMSI (220 mg, 2.00 equiv.), and dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 2h. The reaction was quenched by the addition of 5 mL of a 1M hydrogen chloride aqueous solution, and the mixture was concentrated under vacuum.
  • Step 6 To a 50 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dimethylphenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane 7e (200 mg, 0.59 mmol, 1.00 equiv.), methyl 2,4-difluorobenzoate (153 mg, 0.89 mmol, 1.50 equiv.), CsF (283 mg, 3.00 equiv), and l-Ethyl-3-methylimidazolium dimethyl phosphate (2 mL). The resulting mixture was heated at 90°C overnight.
  • Step 7 To a 50 mL round-bottom flask was added methyl 4-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-dimethylphenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 7f (280 mg, 0.57 mmol, 1.00 equiv.), methanol (2 mL), LiOH (230 mg, 9.60 mmol, 10.00 equiv.), and water (0.2 mL). The resulting mixture was heated at 50°C for 2h.
  • Example 13 4-[(lS,4S,5R)-5- ⁇ [l-(2-chloro-6-methylphenyl)-4-cyclopropyl-1H-pyrazol-5- yl] methoxy ⁇ -2-azabicyclo [2.2. l]heptan-2-yl]-2-fluorobenzoic acid (1-8)
  • Step 7 To a 1000 mL 3 -necked round-bottom flask was added 2-chloro-6-methylaniline 8a (10 g, 70.62 mmol, 1.00 equiv.), a 4M hydrogen chloride aqueous solution (60 mL), and water (45 mL). The mixture was cooled to 0°C, and added slowly with NaNO 2 (4.9 g, 71.01 mmol, 1.00 equiv.), followed by SnCl 2 (19 g, 100.20 mmol, 1.40 equiv.). The resulting mixture was stirred at room temperature for 6h. Solids were collected by filtration.
  • Step 2 To a 100 mL round-bottom flask was added (2-chloro-6-methylphenyl)hydrazine hydrochloride 8b (1.3 g, 6.73 mmol, 1.10 equiv.), ethyl 3-cyclopropyl-4-(dimethylamino)-2- oxobut-3-enoate Id (1.3 g, 6.15 mmol, 1.00 equiv.), ethanol (20 mL), and hydrogen chloride (0.05 mL). The resulting mixture was stirred at room temperature for 4h and then heated at 85°C for 18h.
  • Step 3 To a 100 mL round-bottom flask was added ethyl l-(2-chloro-6-methylphenyl)-4- cyclopropyl-1H-pyrazole-5-carboxylate 8c (900 mg, 2.95 mmol, 1.00 equiv.), tetrahydrofuran (10 g, 138.68 mmol, 46.96 equiv), and DIBAL-H (10 mL, 1M in toluene). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 10 mL of H 2 O, 30 mL of a 1M sodium hydroxide aqueous solution, and 10 mL of H 2 O successively.
  • Step 4 To a 250 mL round-bottom flask was added 1H-l,2,3-benzotriazole (270 mg, 2.27 mmol, 1.00 equiv.) and dichloromethane (50 mL). The solution was cooled to 0°C, and added with thionyl chloride (0.54 g, 2.0 equiv.) dropwise with stirring. [l-(2-chloro-6-methylphenyl)-4- cyclopropyl-1H-pyrazol-5-yl]methanol 8d (600 mg, 2.28 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at room temperature for 2h.
  • Step 5 To a 50 mL round-bottom flask was added l-(2-chloro-6-methylphenyl)-5- (chloromethyl)-4-cyclopropyl-1H-pyrazole 8e (560 mg, 1.99 mmol, 1.00 equiv.), benzyl (1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate C-l (590 mg, 2.39 mmol, 1.20 equiv.), sodium hydride (100 mg, 60% dispersion in mineral oil, 4.17 mmol, 2.00 equiv.), and N,N-dimethylformamide (10 mL).
  • Step 8 To a 25 mL round-bottom flask was added methyl 4-[(1S,4S,5R)-5-[[l-(2-chloro-6- methylphenyl)-4-cyclopropyl-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 8h (91 mg, 0.18 mmol, 1.00 equiv.), methanol (3 mL), water (0.5 mL), and Li OH (75 mg, 3.13 mmol, 10.00 equiv.). The resulting mixture was heated at 50°C for 3h.
  • the mixure was diluted with 10 mL of H 2 O after cooling to room temperature, the pH value of the solution was adjusted to 3 with a 1M aqueous hydrogen chloride solution.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2), dried dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions Column, XBridge Shield RP18 OBD Column,, 5um, 19* 150mm; mobile phase, Water (0.05%TFA ) and ACN (50.0% ACN up to 68.0% in 8 min); Detector, uv 254/220nm.
  • Example 14 4-[(lS,4S,5R)-5- ⁇ [l-(2-chloro-6-fluorophenyl)-4-cyclopropyl-1H-pyrazol-5- yl] methoxy ⁇ -2-azabicyclo [2.2. l]heptan-2-yl]-2-fluorobenzoic acid (1-9)
  • Step 1 To a 250 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added ethyl 3-cyclopropyl-4-(dimethylamino)-2-oxobut-3-enoate Id (2 g, 9.47 mmol, 1.00 equiv.), ethanol (30 mL), (2-chloro-6-fluorophenyl)hydrazine hydrochloride 9a (1.7 g, 8.63 mmol, 1.10 equiv.), and hydrogen chloride (0.14 mL). The resulting mixture was stirred at 25°C for 4h and then heated at 85°C for 18h.
  • Step 2 To a 100 mL round-bottom flask was added ethyl l-(2-chloro-6-fluorophenyl)-4- cyclopropyl-1H-pyrazole-5-carboxylate 9b (1.25 g, 4.05 mmol, 1.00 equiv.), tetrahydrofuran (12 mL), and a 1.5M solution of DIBAL in toluene (5.4 mL, 2.00 equiv.). The resulting mixture was stirred at room temperature for 18h, and quenched by the addition of water (5 mL), a 1M aqueous NaOH solution (15 mL), and water (5 mL) successively.
  • Step 3 To a 100 mL round-bottom flask was added 1H-l,2,3-benzotriazole (399 mg, 3.35 mmol, 1.00 equiv.) and dichloromethane (10 mL). The solution was cooled to 0°C, thionyl chloride (600 mg, 1.50 equiv.) was added, and the mixture was stirred for 0.5 at this temperature. A solution of [l-(2-chloro-6-fluorophenyl)-4-cyclopropyl-1H-pyrazol-5-yl]methanol 9c (900 mg, 3.37 mmol, 1.00 equiv.) in dichloromethane (5 mL) was added.
  • Step 4 To a 100 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added l-(2-chloro-6-fluorophenyl)-5-(chloromethyl)-4-cyclopropyl-1H-pyrazole 9d (560 mg, 1.96 mmol, 1.00 equiv.), benzyl (1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane- 2-carboxylate C-l (584 mg, 2.36 mmol, 1.20 equiv.) and N,N-dimethylformamide (7 mL).
  • Step 5 To a 100 mL round-bottom flask was added benzyl (1S,4S,5R)-5-[[l-(2-chloro-6- fluorophenyl)-4-cyclopropyl-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane-2- carboxylate 9e (430 mg, 0.87 mmol, 1.00 equiv.), dichloromethane (6 mL), and TMSI (348 mg, 1.74 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for 30 min, and quenched by the addition of a 10% of hydrogen chloride aqueous solution.
  • Step 7 To a 25 mL round-bottom flask was added methyl 4-[(1S,4S,5R)-5-[[l-(2-chloro-6- fluorophenyl)-4-cyclopropyl-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 9g (110 mg, 0.21 mmol, 1.00 equiv.), LiOH-H 2 O (90 mg, 2.10 mmol, 10.0 equiv), methanol (2 mL), and water (0.2 mL). The resulting mixture was stirred at 50°C for 2h.
  • Example 15 4-[(lS,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-difluorophenyl)-1H-pyrazol-5- yl]methoxy ⁇ -2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid (1-10)
  • Step 1 To a 100 mL round-bottom flask was added ethyl 3-cyclopropyl-4-(dimethylamino)-2- oxobut-3-enoate Id (1.3 g, 6.15 mmol, 1.00 equiv.), ethanol (23 mL), hydrogen chloride (cat.) (0.09 mL), and (2, 6-difluorophenyl)hydrazine hydrochloride 10a (1.33 g, 7.37 mmol, 1.10 equiv.). The resulting mixture was stirred at room temperature for 4h and then heated at 85°C overnight.
  • Step 2 To a 25 mL round-bottom flask was added ethyl 4-cyclopropyl-l-(2,6-difluorophenyl)- 1H-pyrazole-5-carboxylate 10b (620 mg, 2.12 mmol, 1.00 equiv.), tetrahydrofuran (10 mL), and a 1.5M DIBAL-H solution in Toluene (3.4 mL, 2.40 equiv.). The resulting mixture was stirred at room temperature overnight, then quenched by the addition of 1 mL of 1M NaOH aqueous solution. The mixture was further diluted with water (20 mL), and extracted with ethyl acetate (100 mL x 2).
  • Step 4 To a 50 mL round-bottom flask was added benzyl (1S,4S,5R)-5-hydroxy-2- azabicyclo[2.2.1]heptane-2-carboxylate C-l (250 mg, 1.01 mmol, 1.20 equiv.), 5-
  • Step 6 To a 8 mL sealed tube was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6-difluorophenyl)- 1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane 10f (110 mg, 0.32 mmol, 1.00 equiv.), tert-butyl 4-bromo-2-fluorobenzoate (132 mg, 0.48 mmol, 1.50 equiv.), Pd(OAc) 2 (7.3 mg, 0.10 equiv.), Xantphos (37 mg, 0.06 mmol, 0.20 equiv.), dioxane (1.6 mL), and Cs 2 CO 3 (315 mg, 0.97 mmol, 3.00 equiv.).
  • Step 7 To a 25 mL round-bottom flask was added tert-butyl 4-[(1S,4S,5R)-5-[[4-cyclopropyl-l- (2,6-difluorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 10g (54 mg, 0.10 mmol, 1.00 equiv.), dichloromethane (2 mL), and
  • Step 1 To a 250 mL round-bottom flask was added (1S,4R,5R)-5-hydroxy-2-[(4- methoxyphenyl)methyl]-2-azabicyclo[2.2.1]heptan-3-one C-7 (4 g, 16.18 mmol, 1.00 equiv.), N,N-dimethylformamide (50 mL), TBDPSC1 (4.1 g, 1.30 equiv), and imidazole (1.93 g, 2.50 equiv.). The resulting mixture was stirred at 40°C for 4h. After cooling, the mixture was quenched with water, and extracted with ethyl acetate (200 mL x 2).
  • Step 2 To a 250 mL round-bottom flask was added a solution of (1S,4R,5R)-5-[(tert- butyldiphenylsilyl)oxy]-2-[(4-methoxyphenyl)methyl]-2-azabicyclo[2.2. l]heptan-3-one 11a (1.65 g, 3.40 mmol, 1.00 equiv.) in MeCN (40 mL) and a solution of CAN (7.46 g, 4.00 equiv.) in water(17 mL). The resulting mixture was stirred at room temperature for 30 min.
  • Step 3 To a 50 mL round-bottom flask was added (1S,4R,5R)-5-[(tert-butyldiphenylsilyl)oxy]- 2-azabicyclo[2.2.1]heptan-3-one lib (500 mg, 1.37 mmol, 1.00 equiv.), 1,4-dioxane (10 mL), Pd 2 (dba) 3 (65 mg, 0.07 mmol, 0.05 equiv.), XantPhos (120 mg, 0.15 equiv), Cs 2 CO 3 (670 mg, 2.06 mmol, 1.50 equiv.), and tert-butyl 4-bromobenzoate (421 mg, 1.64 mmol, 1.20 equiv.).
  • Step 4 To a 50 mL round-bottom flask was added a solution of tert-butyl 4-[(1S,4R,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoate 11c (700 mg, 1.29 mmol, 1.00 equiv.) in tetrahydrofuran (1 mL) and TBAF (2 mL, 2.00 equiv). The resulting mixture was stirred at room temperature for lh, quenched with the addition of water (50 mL). The aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate and
  • Step 5 To a 250 mL round-bottom flask was added 5-(chloromethyl)-4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazole lg (1.3 g, 4.31 mmol, 1.00 equiv.), acetone (34 mL), Nal (1.3 g, 8.67 mmol, 2.00 equiv.), and TBAI (400 mg, 1.08 mmol, 0.25 equiv.). The resulting mixture was heated at 62°C for 2h. After cooling to room temperature, the mixture was quenched with 30 mL of water.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 6 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-hydroxy-3-oxo-2- azabicyclo[2.2.1]heptan-2-yl]benzoate lid (86 mg, 0.28 mmol, 1.00 equiv.), AgOTf (435 mg, 2.00 equiv.), 4 A MS (160 mg, 2 w/w), 2,6-di-tert-butylpyridine (310 mg, 6.00 equiv.), dichloromethane (9 mL), and 4-cyclopropyl-l-(2,6-dichlorophenyl)-5-(iodomethyl)-1H-pyrazole lie (220 mg, 0.56 mmol, 2.0 equiv.).
  • Step 7 To a 25 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoate llf (120 mg, 0.21 mmol, 1.00 equiv.), dichloromethane (2 mL), and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for lh, and quenched with water.
  • the aqueous mixture was extracted with ethyl acetate (50 mL x 2), and the combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column,, 5um,19* 150mm; mobile phase, Water(0.1%FA) and ACN (36% ACN up to 40% in 18 min); Detector, UV 254nm.
  • Example 17 4-[(lS,4R,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy ⁇ -3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid (1-12)
  • Step 1 To a 100 mL round-bottom flask was added a solution of (1S,4R,5R)-5-[(tert- butyldiphenylsilyl)oxy]-2-azabicyclo[2.2.1]heptan-3-one lib (570 mg, 1.56 mmol, 1.00 equiv.) in 1,4-dioxane (12 mL), Pd 2 (dba) 3 (71 mg, 0.08 mmol, 0.05 equiv.), XantPhos (135 mg, 0.23 mmol, 0.15 equiv.), Cs 2 CO 3 (762 mg, 2.34 mmol, 1.50 equiv.), and tert-butyl 4-bromo-2- fluorobenzoate (513 mg, 1.86 mmol, 1.20 equiv.).
  • Step 2 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoate 12a (710 mg, 1.27 mmol, 1.00 equiv.), tetrahydrofuran (2.5 mL), and TBAF (662 mg, 2.53 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature for lh, quenched with water.
  • Step 3 To a 100 mL round-bottom flask was added tert-butyl 2-fluoro-4-[(1S,4R,5R)-5- hydroxy-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoate 12b (150 mg, 0.47 mmol, 1.00 equiv.), AgOTf (249 mg, 2.00 equiv.), 4 A MS (300 mg, 2 w/w), 2,6-di-tert-butyl pyridine (558 mg, 6.00 equiv.), dichloromethane (15 mL), and 4-cyclopropyl-l-(2,6-dichlorophenyl)-5-(iodomethyl)- 1H-pyrazole lie (376 mg, 0.96 mmol, 2.00 equiv.).
  • Step 4 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2- fluorobenzoate 12c (90 mg, 0.15 mmol, 1.00 equiv.), dichloromethane (2 mL), and
  • the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19* 150mm; mobile phase, Water (0.05% TFA) and ACN (38.0% ACN up to 57.0% in 8 min); Detector, UV 254/220nm.
  • Step 1 To a 50 mL round-bottom flask was added (1S,4R,5R)-5-[(tert-butyldiphenylsilyl)oxy]- 2-azabicyclo[2.2.1]heptan-3-one 11b (300 mg, 0.82 mmol, 1.00 equiv.), Pd 2 (dba) 3 (39 mg, 0.04 mmol, 0.05 equiv.), XantPhos (75 mg, 0.15 equiv.), Cs 2 CO 3 (411 mg, 1.26 mmol, 1.50 equiv.), 1,4-dioxane (8 mL), and tert-butyl 4-bromo-3-fluorobenzoate (240 mg, 0.87 mmol, 1.20 equiv.).
  • Step 2 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoate 13a (400 mg, 0.71 mmol, 1.00 equiv.), and a solution of TBAF (400 mg, 12.19 mmol, 2.00 equiv.) in tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature for lh, and quenched with water.
  • TBAF 400 mg, 12.19 mmol, 2.00 equiv.
  • Step 3 To a 250 mL round-bottom flask was added tert-butyl 3-fluoro-4-[(1S,4R,5R)-5- hydroxy-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoate 13b (200 mg, 0.62 mmol, 1.00 equiv.), AgOTf (308 mg, 2.00 equiv.), 4 A MS (400 mg, 2.00 equiv.), 2,6-di-tert-butyl pyridine (688 mg, 6.00 equiv.), dichloromethane (20 mL), and 4-cyclopropyl-l-(2,6-dichlorophenyl)-5- (iodomethyl)-1H-pyrazole 11e (488 mg, 1.24 mmol, 2.00 equiv.).
  • Step 4 To a 50 mL round-bottom flask was added tert-butyl 4-[(1S,4R,5R)-5-[[4-cyclopropyl-l- (2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3- fluorobenzoate 13c (170 mg, 0.29 mmol, 1.00 equiv.), dichloromethane (2 mL), and
  • the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19* 150mm; mobile phase, Water(0.05%TFA ) and ACN (5.0% ACN up to 48.0% in 1 min, up to 61.0% in 7 min);
  • Step 1 Ethyl 2-oxoacetate 14c was predistilled at 120 to 130°C. Cyclopenta-l,3-diene 14b was freshly cracked at 175°C. To a 2000 mL round-bottom flask was added tert-butyl N-(triphenyl-
  • [5]-phosphanylidene)carbamate 14a (56.6 g, 149.97 mmol, 1.00 equiv.), toluene (500 mL), cyclopenta-l,3-diene 14b (19.8 g, 299.54 mmol, 2.00 equiv.), and ethyl 2-oxoacetate 14c (30.6 g, 299.74 mmol, 2.00 equiv.).
  • the resulting mixture was stirred at room temperature for 2 days and concentrated under vacuum.
  • Step 2 To a 2000 mL 3-necked round-bottom flask purged with and maintained under an inert atmosphere of nitrogen was added 2-tert-butyl 3-ethyl 2-azabicyclo[2.2.1]hept-5-ene-2,3- dicarboxylate 14d (26.7 g, 99.88 mmol, 1.00 equiv.) and tetrahydrofuran (400 mL, 1.00 equiv.). A 1M solution of BH 3 in THF (110 mL, 1.10 equiv.) was added dropwise with stirring at -78°C, and the mixture was stirred at this temperture for 15 min. The mixture was then allowed to warm to room temperature and stirred for 1 more hour.
  • 2-tert-butyl 3-ethyl 2-azabicyclo[2.2.1]hept-5-ene-2,3- dicarboxylate 14d (26.7 g, 99.88 mmol, 1.00 equiv.)
  • a 2M sodium hydroxide aqueous solution (175 mL, 3.50 equiv.) was added dropwise followed by the addition of a 30% H2O 2 aqueous solution (50 mL, 5.00 equiv.) dropwise with stirring at 0°C.
  • the resulting mixture was stirred for 30 min at room temperature.
  • the mixture was cooled in an ice/water bath, carefully quenched by the addition of 100 mL of a sat.NaHCO 3 aqueous solution, and further diluted with 400 mL of brine.
  • the aqueous mixture was extracted with ethyl acetate (300 mL x 4).
  • Step 4 To a 100 mL round-bottom flask was added 2-tert-butyl 3-ethyl (1S,3S,4S,5R)-5- hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate 14g (2.2 g, 7.71 mmol, 1.00 equiv.), N,N-dimethylformamide (20 mL), imidazole (2.1 g, 4.00 equiv), and TBDPSC1 (4.2 g, 2.00 equiv). The resulting mixture was stirred at 40°C overnight. The mixture was diluted with 50 mL of brine, and extracted with ethyl acetate (250 mL x 3).
  • Step 5 To a 250 mL round-bottom flask was added 2-tert-butyl 3-ethyl (1S,3S,4S,5R)-5-[(tert- butyldiphenylsilyl)oxy]-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate 14h (3.73 g, 7.12 mmol, 1.00 equiv.), tetrahydrofuran (26 mL), and LiBH 4 (389 mg, 2.00 equiv). The resulting mixture was stirred at room temperature overnight, diluted with 50 mL of EA, and then quenched by the addition of 100 mL of a saturated H 4 C1 aqueous solution.
  • the aqueous mixture was extracted with ethyl acetate (200 mL x 2).
  • the combined organic extracts were washed with brine ( 250 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum.
  • Step 6 To a 100 mL round-bottom flask was added tert-butyl (1S,3S,4S,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate 14i (3.31 g, 6.87 mmol, 1.00 equiv.), tetrahydrofuran (42 mL), TEA (3.1 mL, 3.00 equiv.), and
  • Step 7 To a 100 mL round-bottom flask was added tert-butyl (1S,3S,4S,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-[(methanesulfonyloxy)methyl]-2-azabicyclo[2.2.1]heptane-2- carboxylate 14j (3.44 g, 6.15 mmol, 1.00 equiv.), tetrahydrofuran (28 mL), and LiBH 4 (1.1 g, 8.00 equiv.). The resulting mixture was heated at 60°C overnight.
  • Step 8 To a 100 mL round-bottom flask was added tert-butyl (1S,3R,4S,5R)-5-[(tert- butyldiphenylsilyl)oxy]-3-methyl-2-azabicyclo[2.2. l]heptane-2-carboxylate 14k (2.39 g, 5.13 mmol, 1.00 equiv.), tetrahydrofuran (14 mL), and TBAF (10.3 mL, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight, and diluted with water.
  • aqueous mixture was extracted with ethyl acetate (200 mL x 2); and the combined organic extracts were washed with brine (250 mL x 3), dried over anhydrous sodium sulfate and concentrated under vacuum to give tert-butyl (1 S,3R,4S,5R)-5-hydroxy-3-methyl-2-azabicyclo[2.2. l]heptane-2-carboxylate 141 (3.21 g, 99%) as a light yellow oil.
  • Step 9 To a 25 mL round-bottom flask was added 4-cyclopropyl-l-(2,6-dichlorophenyl)-5- (iodomethyl)-1H-pyrazole lie (500 mg, 1.27 mmol, 1.50 equiv.), tert-butyl (1S,3R,4S,5R)-5- hydroxy-3-methyl-2-azabicyclo[2.2.1]heptane-2-carboxylate 141 (600 mg, 0.95 mmol, 1.00 equiv.), N,N-dimethylformamide (1.5 mL), and sodium hydride (69 mg, 60% dispersion in mineral oil, 1.73 mmol, 2.00 equiv).
  • the resulting mixture was stirred at room temperature overnight.
  • the aqueous mixture was diluted with EA (100 mL), and quenched with water.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2).
  • the combined organic extracts were washed with brine (150 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 10 To a 50 mL round-bottom flask was added tert-butyl (1S,3R,4S,5R)-5-[[4-cyclopropyl- l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptane-2- carboxylate 14m (550 mg, 0.67 mmol, 1.00 equiv.), dichloromethane (11 mL), and
  • Step 11 To a 5 mL sealed tube was added (1S,3R,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptane, trifluoroacetic acid salt, 14n (70 mg, 0.14 mmol, 1.00 equiv.), tert-butyl 4-bromobenzoate (54 mg, 0.21 mmol, 1.50 equiv.), Ruphos precatalyst (24 mg, 0.20 equiv.), Ruphos (13 mg, 0.20 equiv.), Cs 2 CO 3 (136 mg, 0.42 mmol, 3.00 equiv), and tol (1 mL).
  • Step 12 To a 25 mL round-bottom flask was added tert-butyl 4-[(1S,3R,4S,5R)-5-[[4- cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-methyl-2- azabicyclo[2.2.1]heptan-2-yl]benzoate 14o (40 mg, 0.07 mmol, 1.00 equiv.), dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL). The resulting mixture was stirred for 1 h at room temperature and quenched with a saturated sodium bicarbonate aqueous solution.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2), and the combined organic extracts were washed with brine (150 mL x 3), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions:
  • Example 20 4-[(lS,3R,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl] methoxy ⁇ -3-methyl-2-azabicyclo [2.2.1] heptan-2-yl] -2-fluorobenzoic acid (1-15)
  • Step 1 To an 8 mL sealed tube was added tert-butyl 4-bromo-2-fluorobenzoate (156 mg, 0.57 mmol, 1.50 equiv.), (1S,3R,4S,5R)-5-[[4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptane, trifluoroacetic acid salt 14m (150 mg, 0.30 mmol, 1.00 equiv.), Ruphos precatalyst (63 mg, 0.20 equiv.), Ruphos (36 mg, 0.20 equiv.), Cs 2 CO 3 (367 mg, 1.13 mmol, 3.00 equiv.), and toluene (2.5 mL).
  • tert-butyl 4-bromo-2-fluorobenzoate 156 mg, 0.57 mmol, 1.50 equi
  • Step 2 To a 25 mL round-bottom flask was added tert-butyl 4-[(1S,3R,4S,5R)-5-[[4- cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-methyl-2- azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoate 15a (130 mg, 0.22 mmol, 1.00 equiv.), dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for lh and quenched with the addition of a saturated sodium bicarbonate aqueous solution.
  • the aqueous mixture was extracted with ethyl acetate (100 mL x 2).
  • the combined organic extracts were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column,, 5um,19* 150mm; mobile phase, Water(0.05%TFA ) and ACN (52.0% ACN up to 70.0% in 8 min); Detector, UV 254/220nm.
  • Step 1 To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added tert-butyl 3-ethyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate 14e (185 mg, 0.77 mmol, 1.00 equiv.), 4-cyclopropyl-l-(2,6-dichlorophenyl)-5-(iodomethyl)-1H- pyrazole lie (600 mg, 1.53 mmol, 2.00 equiv.), N,N-dimethylformamide (4 mL), and sodium hydride (70 mg, 60% dispersion in mineral oil, 1.67 mmol, 2.00 equiv.).
  • the resulting mixture was stirred at room temperature for 4 h.
  • the mixture was diluted with EA (20 mL), then quenched by the addition of water (10 mL), and extracted with ethyl acetate (100 mL x 2).
  • the combined organic extracts were washed with brine (50 mL x 4), dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step 3 To a 25 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was added 5-[[4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3- ethyl-2-azabicyclo[2.2.1]heptane 16b (120 mg, 0.30 mmol, 1.00 equiv.), tert-butyl 4- bromobenzoate (118 mg, 0.46 mmol, 1.50 equiv), Ruphos (27 mg, 0.06 mmol, 0.20 equiv), Cs 2 CO 3 (287 mg, 0.88 mmol, 3.00 equiv.), toluene (2.5 mL), and Ruphos-precatalyst (50 mg, 0.06 mmol, 0.20 equiv.).
  • Step 5 The racemic mixture of acids 16d was separated by Chiral-Prep-HPLC using the following conditions (Prep-HPLC-004): Column, CHIRALPAK IC, 2*25cm,5um; mobile phase, Hex(0.1%FA)- and ethanol- (hold 20.0% ethanol- in 16 min); Detector, UV 220/254nm.
  • Example 22 4-[(lS,3R,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy ⁇ -3-ethyl-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid (1-18) and 4- [(lR,3S,4R,5S)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy ⁇ -3- ethyl-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid (1-19)
  • Step 1 To a 50 mL round-bottom flask was added Cs 2 CO 3 (480 mg, 1.47 mmol, 3.00 equiv.), toluene (4 mL), tert-butyl 4-bromo-2-fluorobenzoate (162 mg, 0.59 mmol, 1.20 equiv.), 5-[[4- cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-ethyl-2- azabicyclo[2.2.1]heptane trifluoro acid acid salt 16b (200 mg, 0.49 mmol, 1.00 equiv.), Ruphos (82.3 mg, 0.20 equiv.), and Rupos preacatalyst (46 mg, 0.20 equiv.). The resulting mixture was heated at 110°C overnight. After cooling to room temperature, the mixture was diluted with
  • Step 2 To a 50 mL round-bottom flask was added tert-butyl 4-(5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-3-ethyl-2-azabicyclo[2.2.1]heptan-2-yl)-2- fluorobenzoate 18a (180 mg, 0.30 mmol, 1.00 equiv.), trifluoroacetic acid (2 mL), and dichloromethane (4 mL). The resulting mixture was stirred at room temperature for lh.
  • Example 23 4-[(lS,4S,5R)-5- ⁇ [4-cyclopropyl-l-(2,6-dichlorophenyl)-1H-pyrazol-5- yl]methoxy ⁇ -2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxane-4-sulfonyl)benzamide (1-20)
  • the aqueous mixture was extracted with ethyl acetate (100 mL), and the organic extract was washed with a 1M hydrogen chloride aqueous solution (20 mL x 2) followed by brine (20 mL x 2).
  • the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the residue was dissolved in 3 mL of DMF and purified by Prep-HPLC using the following conditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19* 150mm; mobile phase, Water (0.05% TFA) and ACN (48.0% ACN up to 56.0% in 10 min); Detector, uv 254nm.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des activateurs de FXR utiles dans le traitement de troubles auto-immuns, de maladies hépatiques, de maladies intestinales, de l'insuffisance rénale, du cancer et d'autres maladies dans lesquelles le FXR joue un rôle, ayant la formule (I) : dans laquelle L1, A, X1, X2, Y1, Y2, Y3, Y4, R1, R2, et R3 sont définis dans la description.
EP18779987.9A 2017-09-14 2018-09-14 Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques mutagènes et fibrotiques Active EP3681881B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762558858P 2017-09-14 2017-09-14
PCT/US2018/051122 WO2019055808A1 (fr) 2017-09-14 2018-09-14 Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques mutagènes et fibrotiques

Publications (2)

Publication Number Publication Date
EP3681881A1 true EP3681881A1 (fr) 2020-07-22
EP3681881B1 EP3681881B1 (fr) 2022-11-02

Family

ID=63714148

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18779987.9A Active EP3681881B1 (fr) 2017-09-14 2018-09-14 Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques mutagènes et fibrotiques

Country Status (6)

Country Link
US (1) US11753410B2 (fr)
EP (1) EP3681881B1 (fr)
JP (2) JP7271513B2 (fr)
CN (1) CN111655680B (fr)
MA (1) MA50242A (fr)
WO (1) WO2019055808A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11091482B2 (en) 2016-08-23 2021-08-17 Ardelyx, Inc. Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators
CN110128432B (zh) 2018-02-02 2021-03-02 广东东阳光药业有限公司 含氮三环化合物及其在药物中的应用

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1228288B (it) 1989-01-09 1991-06-07 Zambon Spa Composti ad attivita' antiserotoninica
US5262564A (en) 1992-10-30 1993-11-16 Octamer, Inc. Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents
TW200906823A (en) 2007-07-16 2009-02-16 Lilly Co Eli Compounds and methods for modulating FXR
EP2289883A1 (fr) * 2009-08-19 2011-03-02 Phenex Pharmaceuticals AG Nouveaux composés modulant l'activité du recepteur FXR (NR1H4)
CN103391937A (zh) 2010-12-20 2013-11-13 Irm责任有限公司 用于调控法尼醇x受体的组合物和方法
JP2014500318A (ja) 2010-12-20 2014-01-09 アイアールエム・リミテッド・ライアビリティ・カンパニー ファルネソイドｘ受容体を調節するための組成物および方法
CU24152B1 (es) * 2010-12-20 2016-02-29 Irm Llc 1,2 oxazol-8-azabiciclo[3,2,1]octano 8 il como moduladores de fxr
WO2013072693A1 (fr) 2011-11-15 2013-05-23 Xention Limited Thiéno[2,3-c]pyrazoles destinés à être utilisés comme inhibiteurs des canaux potassiques
EP3034501A1 (fr) * 2014-12-17 2016-06-22 Gilead Sciences, Inc. Hydroxy contenant des composés de modulation (FXR NR1H4)
SG11201704340VA (en) * 2014-12-18 2017-07-28 Novartis Ag Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases
TWI698430B (zh) 2015-02-13 2020-07-11 南北兄弟藥業投資有限公司 三環化合物及其在藥物中的應用
EP3504205B1 (fr) 2016-08-23 2021-08-04 Ardelyx, Inc. Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques
US11091482B2 (en) 2016-08-23 2021-08-17 Ardelyx, Inc. Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators
BR112020000180A2 (pt) 2017-07-06 2020-07-14 Xuanzhu (Hainan) Biopharmaceutical Co., Ltd. agonista do receptor fxr

Also Published As

Publication number Publication date
JP2020534275A (ja) 2020-11-26
US11753410B2 (en) 2023-09-12
WO2019055808A1 (fr) 2019-03-21
EP3681881B1 (fr) 2022-11-02
MA50242A (fr) 2020-07-22
JP7271513B2 (ja) 2023-05-11
CN111655680B (zh) 2024-03-05
JP2023065577A (ja) 2023-05-12
US20210380585A1 (en) 2021-12-09
CN111655680A (zh) 2020-09-11

Similar Documents

Publication Publication Date Title
US11718619B2 (en) Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators
CN108064223B (zh) 含羟基的fxr(nr1h4)调节化合物
CN109071468B (zh) 一种杂环化合物及其制备方法和用途
JP6484632B2 (ja) Ｔｎｆ活性のモジュレーターとしてのテトラヒドロイミダゾピリジン誘導体
EP3504205A1 (fr) Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques
RU2679609C1 (ru) Производные имидазопиридазина в качестве модуляторов активности tnf
RU2677697C1 (ru) Производные триазолопиридина в качестве модуляторов активности tnf
JP2018504432A (ja) ユビキチン特異的プロテアーゼ７阻害物質としてのイソチアゾロピリミジノン、ピラゾロピリミジノン及びピロロピリミジノン
RU2677698C1 (ru) Производные триазолопиридазина в качестве модуляторов активности tnf
JP2023065577A (ja) 代謝関連の突然変異誘発性及び線維性の症状及び障害を治療するためのホルモン受容体調節薬
JP6908623B2 (ja) テトラヒドロイソキノリン誘導体
AU2006298164A1 (en) Novel fused pyrrole derivative
AU2018357878A1 (en) Spirocyclic compounds as farnesoid X receptor modulators
WO2017134555A1 (fr) Dérivés de pyrroloimidazole ou analogues de ceux-ci utiles, entre autres, dans le traitement du cancer
WO2019089670A1 (fr) Composés d'alcène utilisés en tant que modulateurs du récepteur farnésoïde x
WO2019089665A1 (fr) Composés spirocycliques d'alcène en tant que modulateurs du récepteur farnésoïde x
WO2018109271A1 (fr) Nouveaux inhibiteurs de bromodomaines
CN116635028A (zh) c-MYC mRNA翻译调节剂及其在治疗癌症中的用途
WO2021113368A1 (fr) Antagonistes de sstr5
CA3236877A1 (fr) Composes heterocycliques et leurs utilisations
WO2023129553A1 (fr) Inhibiteurs de bcl-2
WO2023077070A1 (fr) Agonistes de rxfp1

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200310

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20220422

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 1528674

Country of ref document: AT

Kind code of ref document: T

Effective date: 20221115

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602018042596

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20221102

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1528674

Country of ref document: AT

Kind code of ref document: T

Effective date: 20221102

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230302

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230202

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230302

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20230203

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230525

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602018042596

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20230803

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20230927

Year of fee payment: 6

Ref country code: GB

Payment date: 20230927

Year of fee payment: 6

VS25 Lapsed in a validation state [announced via postgrant information from nat. office to epo]

Ref country code: MD

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20221102

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20230925

Year of fee payment: 6

Ref country code: DE

Payment date: 20230927

Year of fee payment: 6

Ref country code: BE

Payment date: 20230927

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20231004

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230914